To examine the frequency and significance of alpha-fetoprotein (AFP) elevation, radioimmunoassay for AFP was performed every 3-6 months in a prospective follow-up study on 432 hepatitis B surface antigen (HBsAg)-positive and 105 HBsAg-negative patients with clinicopathologically proven chronic hepatitis. In a period of 6-85 months (mean 26.9 +/- 16.8), AFP elevation (greater than 20 ng/ml) was recorded in 45.6% of the HBsAg-positive patients. In addition, 19.4% of the HBsAg-positive patients had AFP levels greater than 100 ng/ml, with a highest level of 2520 ng/ml in the absence of hepatocellular carcinoma (HCC). All these figures were much greater than those for HBsAg-negative patients (P less than 0.001). Most episodes of AFP elevation were transient, with parallel moderate SGPT elevation (greater than 200 IU/L). The AFP levels in such episodes correlated closely with the presence of bridging hepatic necrosis, only weakly with peak SGPT levels, but not with age, sex or hepatitis B e antigen/antibody status. None of the transient episodes was followed by subsequent development of HCC. On the other hand, AFP elevation (greater than 100 ng/ml) without parallel SGPT elevation could predict the presence of HCC with very high specificity (98.7%). However, the sensitivity was not high enough (66.7%) for one to rely solely on AFP for the detection of HCC at its earlier stage.